Two novel SHP-1 agonists, SC-43 and SC-78, are more potent than regorafenib in suppressing the in vitro stemness of human colorectal cancer cells

• Published in: Cell death discovery 2018-08, Vol.4 (1), p.25-12, Article 82
• Main Authors: Chung, Shin-Yi, Chen, Yen-Hsi, Lin, Pei-Rong, Chao, Ta-Chung, Su, Jung-Chen, Shiau, Chung-Wai, Su, Yeu
• Format: Article
• Language: English
• Subjects: 631/532/71; 631/67; Antitumor agents; Apoptosis; Biochemistry; Biomedical and Life Sciences; CD44 antigen; Cell Biology; Cell Cycle Analysis; Clinical trials; Colorectal cancer; Colorectal carcinoma; GLP-1 receptor agonists; Interleukin 6; Irinotecan; Kinases; Life Sciences; Metastases; Oxaliplatin; Phosphorylation; SHP-1 protein; Stat3 protein; Stem Cells; Targeted cancer therapy; Transcription
• ISSN: 2058-7716; 2058-7716
• DOI: 10.1038/s41420-018-0084-z

Signal transducer and activator of transcription 3 (STAT3) has been shown to play a critical role in the maintenance of cancer stem cells (CSCs). Hence, the inhibition of STAT3 signaling has been suggested to be a viable therapeutic approach for cancers. Moreover, the efficacy of combinations of chemotherapeutic drugs and napabucasin, a small-molecule STAT3 inhibitor, have been assessed in various clinical trials, including those involving patients with metastatic colorectal cancer (CRC). Two recently developed small-molecule STAT3 inhibitors, SC-43 and SC-78, which can stimulate SHP-1 to inactivate STAT3, were found to have anti-tumor activity. In this study, the inhibitory effects of SC-43, SC-78, and regorafenib (a reference drug) on cell viability, STAT3 phosphorylation, and various stemness properties [e.g., sphere-forming and soft agar colony-forming abilities, CD133 + /CD44 + (stem cell-like) subpopulations, and the expression of several CSC markers] were examined for both HCT-116 and HT-29 human CRC cells. We found that SC-43 and SC-78 but not regorafenib inhibited constitutive and IL-6-induced STAT3 phosphorylation in HCT-116 and HT-29 cells, respectively. Moreover, SC-43 and SC-78 were more potent than regorafenib in suppressing the stemness properties (except stem cell-like subpopulations) of these cells. As expected, SHP-1 knockdown almost completely abolished the suppressive effects of SC-43 and SC-78 on the sphere formation in both cell lines. Furthermore, SC-43 and SC-78 showed synergistic inhibitory effects with oxaliplatin and/or irinotecan on sphere formation. Overall, our results suggest that SC-43 and SC-78 are potent STAT3 inhibitors that may potentially be used in combination therapy for CRC.